Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH3:34][N:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:36](=[O:38])[CH3:37]>CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([N:35]([CH3:34])[C:36](=[O:38])[CH3:37])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4N(C)C(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 45.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give, after chromatography on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution, the title compound; Rf=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution).
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[C:7]([I:21])=[C:8]([C:12]([I:20])=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[C:14]=1[I:15])[C:9]([OH:11])=[O:10])(=[O:4])[CH3:3].Cl[CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O:10][C:9](=[O:11])[C:8]1[C:7]([I:21])=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[C:14]([I:15])=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[C:12]=1[I:20]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Reactant: OCC(O)CCl
Agent: [Na]
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)OCC(O)CO)c1I

Procedure:
20 g (29 mmol) 3,5-diacetylamino-2,4,6-triiodobenzoic acid-2,3-dihydroxypropyl ester, which can be obtained from the sodium salt of 3,5-diacetylamino-2,4,6-triiodobenzoic acid by reaction with 3-chloropropane-1,2-diol at 105° C. (analogous to Organikum, 12th Edition, Deutscher Verlag der Wissenschaften, Berlin 1973, p.227 et seq.), are dissolved in 80 ml absolute pyridine and cooled to -10° C. To this solution is added dropwise 20 g (130 mmol) of commercially available methacrylic acid anhydride (Fluka) and the mixture is then stirred overnight at room temperature. The resulting clear reaction mixture is mixed with 1 l dilute hydrochloric acid and the white precipitate which forms is filtered off, washed with water to neutral and then reprecipitated from methanol/water. After drying in a fine vacuum (approx. 1 mbar, at room temperature) to a constant weight, 16.1 g (67.1%) colourless powder of amorphous appearance with a DSC melting point of 207° C. is obtained. 1 g of the substance is compressed as described in Example 1 into a tablet and irradiated; there is no discoloration.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 4 h

Procedure:
1-Benzenesulfonylindole-3-carboxylic acid (3.01 g, 0.01 moles) was stirred with oxalyl chloride (1.309 g, 0.011 moles) in 20 mL dichloromethane at 0 to 25° C. for 3-4 hours. After completion of the reaction (T.L.C.), volatile substances were distilled off under the reduced pressure. The residue was taken in 20 mL dichloroethane and to this stirred solution, was added N-methylpiperazine (1.1 g, 0.011 moles). The reaction mixture was further stirred for next 3-5 hours till the reaction completes (TLC). Reaction mixture was diluted with dichloromethane 20 mL), washed with water, brine and saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and the organic solvents were evaporated under vacuo. The product was purified using column chromatography on silica gel G stationary phase and suitable combinations of ethyl acetate and methanol in increasing gradient as the mobile phase. IR spectra (cm−1) 3140, 1621, 1552, 1451; Mass (m/z): 484 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([N:27]=1)[C:20]1([CH2:23][O:22][CH2:21]1)[C:19]([CH3:25])([CH3:24])[O:18][C:17]1[C:12]2=[CH:13][C:14]([NH2:26])=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([N:27]=1)[C:20]1([CH2:23][O:22][CH2:21]1)[C:19]([CH3:25])([CH3:24])[O:18][C:17]1[C:12]2=[CH:13][C:14]([NH:26][C:36]([C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][N:34]=2)=[O:37])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of tert-butyl[(4S)-6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.00 g, 2.57 mmol) and CH2Cl2 (10 mL) were added 5-chloro-2-pyridinecarboxylic acid (526 mg, 3.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole (451 mg, 3.34 mmol) and N,N-diisopropylethylamine (0.571 mL, 3.34 mmol) at ambient temperature. After stirring overnight at the same temperature, the reaction mixture was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) and then on NH-silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to give tert-butyl[(4S)-6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.02 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14]([NH:17][C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[CH:20]=2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].[C:43]([OH:46])(=[O:45])[CH3:44]>CN(C)C=O.CO>[C:8]1([S:14]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]3[N:25]=[C:44]([C:43]([OH:46])=[O:45])[N:26]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:30][CH:29]=4)[C:21]=3[CH:20]=2)=[O:40])(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(C(=O)O)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.080 g) and 0.148 g of methyloxalyl chloride were added to a solution of 0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 3 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to obtain crude 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole. This compound was dissolved in 1 ml of acetic acid and 5 ml of methanol, and the mixture was stirred at 60° C. for 15 hours. The reaction solution was neutralized with a potassium hydroxide aqueous solution. The crystals precipitated were separated through filtration, and were dried to give 0.245 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole (229).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:50]=[CH:49][CH:48]=[CH:47][C:7]=1[C:8]([NH:10][C:11]1[CH:44]=[CH:43][C:14]([C:15]([N:17]([CH3:42])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]([CH3:41])[CH3:40])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:45][CH3:46])=[O:9].CO[C:53](=[NH:55])[NH2:54]>C(O)C>[NH:1]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:50]=[CH:49][CH:48]=[CH:47][C:7]=1[C:8]([NH:10][C:11]1[CH:44]=[CH:43][C:14]([C:15]([N:17]([CH3:42])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]([CH3:40])[CH3:41])[CH2:35][CH2:34]2)=[O:32])=[O:16])=[CH:13][C:12]=1[O:45][CH3:46])=[O:9])[C:53]([NH2:55])=[NH:54]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1OCCCN
Reactant: COC(=N)N
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(N(C)C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=N)N
Yield: 18.2 %

Procedure:
A mixture of 4-[2-(3-aminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-dimethylaminopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (275 mg) and O-methylisourea (44 mg) in ethanol (5 ml) was refluxed for 3 days. The solvent was evaporated in vacuo and the residue was purified on basic silica gel column chromatography (SiO2 17 g, 1-80% methanol in chloroform) to give 4-[2-(3-guanidinoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-dimethylaminopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (53 mg).
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[CH3:10][C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].Cl>CC(C)=O>[OH:4][N:3]=[C:17]([C:18]#[N:19])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[CH2:14][O:13][C:12]1[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=1[CH3:10]
Reactant: Cc1ccccc1OCc1ccccc1CC#N
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccccc1OCc1ccccc1C(C#N)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Acetone (5 ml), 85% potassium hydroxide (powder)(0.40 g, 6 mmol) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2-methylphenoxymethyl)benzyl cyanide (1.19 g, 5 mmol). The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 1N aqueous hydrochloric acid solution (100 ml) was added. The mixture was extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane/chloroform) to give α-hydroxyimino-2-(2-methylphenoxymethyl)benzyl cyanide (1.23 g, Yield: 92.4%, E/Z=35/65) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:22]=1[O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2ccc3ccccc3c2)C1
Yield: 53.8 %

Procedure:
The procedure is the same as for Example 1 (Stage 1.2) starting from 2.00 g (9.94 mmol) of tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (commercial), 2.00 g (13.91 mmol) of naphth-2-ol, 3.90 g (14.91 mmol) of triphenylphosphine and 3.01 g (14.91 mmol) of diisopropyl azodicarboxylate. 1.75 g of product are obtained in the form of an oil after purification on a column of silica gel, elution being carried out with dichloromethane.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[CH2:21][O:20][C:19]([C:22]4[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=4[F:29])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CO.C[O-].[Na+].C(O)(=O)C>O>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[C:19]1[O:20][CH2:21][C@H:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([SH:4])=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[N:18]=1
Reactant: CN(C)C(=O)Sc1ccc(-c2ccc([C@H]3COC(c4c(F)cccc4F)=N3)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(F)c1C1=N[C@@H](c2ccc(-c3ccc(S)cc3)cc2)CO1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.7 %

Procedure:
A mixture of 0.60 g of (S)-S-[4'-[2-(2,6-difluorophenyl)-4,5-dihydro-4-oxazolyl][1,1'-biphenyl]-4-yl] dimethylcarbamothioate, 5 mL of methanol, and 0.30 g of 25% NaOMe solution was heated at 60° C. for 7 h and allowed to stand at ambient temperature for 3 d. After adding 0.5 mL of acetic acid and 5 mL of water, the product was filtered, washed with water, and suction-dried to afford 0.30 g of product, m.p. 133-135° C. The 1H NMR (CDCl3) spectrum was the same as that of the racemic product of Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Br)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-bromophenol (1.73 g) and tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.0 g) in tetrahydrofuran (50 ml),triphenylphosphine (3.1 g) and a solution of diisopropyl azodicarboxylate (2.4 g) in tetrahydrofuran (10 ml) were added, and the mixture was heated to reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (3.5 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[OH-].[NH4+].[CH3:35][O:36][C:37]1[CH:43]=[C:42]([C:44]2[CH2:45][N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH:49]=2)[CH:41]=[CH:40][C:38]=1[NH2:39]>>[F:31][C:29]1[C:28]([F:32])=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[C:22]([NH:21][C:4]2[N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([C:44]4[CH2:45][N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH:49]=4)=[CH:43][C:37]=3[O:36][CH3:35])[NH:7][C:6]3=[N:8][CH:9]=[CH:10][C:5]=23)[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)c(F)cc4C(N)=O)nc(Cl)nc32)cc1
Reactant: CCCN1CCC=C(c2ccc(N)c(OC)c2)C1
Agent: [NH4+]
Agent: [OH-]
Product: CCCN1CCC=C(c2ccc(Nc3nc(Nc4cc(F)c(F)cc4C(N)=O)c4ccnc-4[nH]3)c(OC)c2)C1
Yield: 11.9 %

Procedure:
According to General Protocol III, 4,5-difluoro-2-[4(2-{[2-(methyloxy)-4-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,5-difluorobenzamide (0.300 g, 0.630 mmol), 27% aqueous ammonium hydroxide, and 2-(methyloxy)-4-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)aniline (0.250 g, 0.950 mmol) and isolated as a yellow solid (0.040 g, 12% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.14 Hz, 3H), 1.54 (s, 2H), 1.74 (s, 2H), 2.25 (s, 2H), 2.42 (s, 2H), 3.26 (s, 2H), 3.88 (s, 3H), 6.14 (s, 1H), 6.23-6.32 (m, 1H), 6.93 (d, J=7.69 Hz, 1H), 7.02 (s, 2H), 7.76 (s, 1H), 7.91 (dd, J=1.65, 0.92 Hz, 1H), 7.97 (dd, J=11.72, 8.79 Hz, 1H), 8.12 (d, J=8.42 Hz, 1H), 8.33 (s, 1H), 9.08 (dd, J=14.65, 7.69 Hz, 1H), 11.43 (s, 1H), 12.25 (s, 1H). ESI-MS (M+H) 533. Retention time 1.75 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:4]=2[CH:3]=1>Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: Cl
Product: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Temperature: 50 °C
Yield: 83 %

Procedure:
(S)-Methyl 2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (21 mg, 0.05 mmol) was dissolved in 1N hydrochloric acid (1.0 mL). Reaction was heated at 50° C. for 5 hours. Another 1 mL of 1N hydrochloric acid was added to the mixture. Reaction was heated at 50° C. for 17 hours. Mixture was concentrated in vacuo. Residue was treated with acetonitrile and then the material was concentrated. Title compound was obtained as dark yellow solid in 83% yield. MS m/e (M+H)+=385.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12](N)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.N([O-])=O.[Na+].[FH:28]>>[F:28][C:12]1[N:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: F
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine (1.2 g, 5.0 mmol) in hydrogen fluoride.pyridine (15 mL) is cooled to 0° C. in an ice-water bath. Sodium nitrite (0.36 g, 5.2 mmol) is added in a single portion, and the mixture is stirred for 30 minutes at 0° C. The bath is removed and the mixture is heated for 15 minutes in an oil bath on a 70° C. hot plate. After cooling to room temperature, the reaction mixture is poured onto ice (50 g), neutralized with saturated aqueous sodium hydrogen carbonate solution, and basified with 10 N sodium hydroxide solution. The mixture is extracted 3× with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Eighty-percent of the crude residue is purified by reverse-phase HPLC to give 1-(6-fluoro-5-nitropyridin-2-yl)-4-methylpiperazine.trifluoroacetic acid salt (0.40 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cn2)N1
Reactant: COc1ccc(CCl)c(OC)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cn2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.72 g (20.92 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step F) in DMF (˜0.5M) at 0° C. was slowly added a dispersion of 60% sodium hydride in mineral oil (2.51 g, 62.8 mmol). The reaction was stirred 0° C. for 30 min, followed by addition of 1-(chloromethyl)-2,4-dimethoxybenzene (7.81 g, 41.8 mmol). Upon completion, the reaction was quenched at 0° C. with a small excess of acetic acid (4.79 mL, 84 mmol). It was neutralized with sat. aq. NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and the filtrate as concentrated under reduced pressure to yield a reddish oil. Purification by flash chromatography on silica gel (eluent: 0 to 30% ethyl acetate/DCM, gradient elution) provided the title compound as a pale yellow oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].Br[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CC(C)=O>[CH2:7]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:1][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1c[nH]c2ccccc2c1=O
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1cn(Cc2ccc(C#N)cc2)c2ccccc2c1=O
Reaction time: 0.17 h
Yield: 113.4 %

Procedure:
3.3 g of activated potassium carbonate were added to a suspension of 2.3 g of the product of Step E in 50 ml of acetone a the mixture was stirred for 10 minutes. Then, 4.7 g of 4-bromobenzonitrile were added, followed by heating for 4 hours at reflux. The acetone was evaporated off and the residue was taken up in 100 ml of water. Extraction was carried out with ethyl acetate and the extracts were washed with a saturated solution of ammonium chloride, dried and evaporated to dryness to obtain 4.1 g of the expected product which was chromatographed on silica (eluant: methylene chloride-methanol (98-2)) to obtain 3.3 g of the desired product melting at 168° C.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:27][C:28]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][CH:2]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([O:30][C:28]([O:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:32][CH:33]=2)=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCC(C)OC(=O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC(C)CCCCCC)cc2)cc1
Reaction time: 2 h
Yield: 28.2 %

Procedure:
Optically active 4-(1-methylheptyloxycarbonyl)phenol (10 g, 0.04 mol) was dissolved in pyridine (70 ml), followed by dropwise adding to the solution, under cooling, 4-octyloxycarbonyloxybenzoic chloride (11.4 g, 0.035 mol) prepared in the same manner as in the paragraph (ii) of Example 1, agitating the mixture at 50°-60° C. for 2 hours, placing water and toluene in the reaction solution after completion of the reaction, sufficiently agitating the mixture, washing the separated toluene layer with 6N--HCl, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, drying the resulting toluene layer with anhydrous sodium sulfate, distilling off toluene to obtain a raw objective product, and recrystallizing this product from ethanol to obtain optically active 4-octyloxycarbonyloxybenzoic acid 4-(1-methylheptyloxycarbonyl)phenyl ester (5.2 g), which exhibited no liquid crystal phase and had a m.p. of 33.0° C. Further, by replacing octyl chloroformate used, by other alkyl chloroformates, various optically active 4-alkyloxycarbonyloxybenzoic acid 4-(1-methyl-heptyloxycarbonyl)phenyl esters are obtained. The phase transition points thereof are shown in Tables 1 and 2.